Laboratory of Oncology

Research Outline

Our research mainly focuses on “cancer.” We are studying cancer biology at the molecular level in order to identify new therapeutic targets and strategies for cancer. Furthermore, based on our findings, we are developing new candidates for anticancer drugs by screening for bioactive natural compounds in microbial cultures using our original experimental systems.

Theme

  1. Cancer research targeting tumor-stroma interactions
    • a) Regulation of tumor–stromal cell interactions
    • b) Relationship between chronic inflammation and tumors
    • c) Augmentation of innate immunity
    • d) Development of experimental animal models
    • e) Supporting the activity of cancer researchers
  2. Screening for 3D-sphere formation inhibitors of transformed EGFRvIIIdependent cells
  3. Search and development of drugs for non-communicable diseases with emphasis on cancer, employing cell-based screening systems

Theme outline

1. Cancer research targeting tumor-stroma interactions.

  • Most of the solid tumors originate from epithelial layers, and the tumor tissues consist of not only tumor cells but also stroma surrounding the tumor cells. Stroma includes various types of components such as blood vessels, macrophages, fibroblasts, and extracellular matrix. The stroma regulates tumor development through diffusible factors and direct adhesion. Thus, these tumor–stroma interactions are closely associated with the growth and metastasis of tumor cells. It is noteworthy that tumor–stroma interactions can both accelerate and suppress tumor growth. We hypothesized that manipulation of the interactions between tumor cells and non-tumor host cells such as stroma results in the suppression of tumors. In order to achieve our goal, we are conducting experiments for the following: (a) regulation of tumor–stromal cell interactions, (b) relationship between chronic inflammation and tumors, (c) augmentation of innate immunity, and (d) development of experimental animal models.

Fig.1 Tumor-stromal cell interactions
view

2. Screening for 3D-sphere formation inhibitors of transformed EGFRvIII -dependent cells

  • EGFRvIII is a mutant form of the epidermal growth factor receptor (EGFR) gene that lacks a ligand binding site.EGFRvIII expression is believed to be limited to cancer cells and is found in >30% of all glioblastomas, which are intractable and malignant. It also appears in non-small-cell lung, breast, oral, and thyroid carcinomas. Cells overexpressing EGFRvIII were able to grow in an anchorage-independent fashion and form spheres, a feature of cancer cells, whereas anchorage-dependent parent cells were killed on ultra-low attachment plates (3D cultures). Cells overexpressing EGFRvIII were tumorigenic in athymic nude mice. Thus, we have developed a high-throughput screening method to identify substances that inhibit 3D-sphere formation induced by EGFRvIII without affecting the normal 2D-growth of parent cells on cell adhesion surface plates. We are now screening for inhibitors from various sources, including microbial metabolites.

Fig.2 Screening for inhibitors of 3D-sphere formation induced by EGFRvIII expression
view

3. Search and development of drugs for non-communicable diseases with emphasis on cancer, employing cell-based screening systems

  • Using the world’s top class collections of actinomycete strains and secondary metabolites of BIKAKEN, the screenings of drugs for cancer and other noncommunicable diseases are being conducted in our laboratory. At present, a parallel search for cancer drugs targeting molecules such as EGFR, tubulin, MEK, PI3K, proteasome, HDAC, HSP90, and DNA and its binding proteins as well as for cardiotonic drugs, analgesics, hypolipidemics, and drugs for neurodegenerative diseases is being conducted. The promising new compounds' structure and bioactivities found in these screenings are evaluated for practical use for which each drug is best suited. The new enzyme-stable trehalose analog lentztrehalose is now under investigation for development as a substitute for trehalose or as drugs for neurodegenerative diseases.

Fig.3 Novel trehalose analogs lentztrehalose A, B, and C
view